Efficacy of alectinib in lung adenocarcinoma patients with different anaplastic lymphoma kinase (ALK) rearrangements and co-existing alterations-a retrospective cohort study

Abstract

Background: Alectinib significantly improves survival of non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-rearrangement. In this study, we analyzed the effects of different ALK rearrangements and co-mutations on the efficacy of alectinib.

Methods: Using the electronic medical record system, we reviewed in terms of clinical and pathological features patients with advanced (IIIB/IV stage) ALK-rearranged NSCLC at Shanghai Chest Hospital between January 2018 and December 2021 who were treated with alectinib in first or second line and were assessed for objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).

Results: A total of 66 patients were enrolled in the study, and 17 types of ALK rearrangements were detected, of which five types of ALK rearrangements responded well to alectinib. We classified ALK-rearrangements into four main types, namely echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others. There was no significant difference in ORR and DCR of these types (ORR: 31.3% vs. 13.0% vs. 18.2% vs. 17.6%, P=0.575; DCR: 93.8% vs. 95.6% vs. 100.0% vs. 88.2%, P=0.627). The 3-year PFS rates were 25.0% (4/16) vs. 13.0% (3/23) vs. 27.3% (3/11) vs. 18.8% (3/16) for EML4-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others, respectively (P=0.725). The results of co-mutation analysis showed that the median PFS (mPFS) for patients with tumors harboring TP53 mutations was 30.4 months, significantly shorter than that of patients with tumors without co-mutations and whose mPFS was not mature (P=0.026). TSC1 co-mutation was also identified as a detrimental factor in outcome, with a DCR of 60% vs. 100% (P=0.031), mPFS of 30.4 months vs. not applicable (P=0.160) in patients with vs. those without this co-mutation, respectively. The efficacy of alectinib in patients with brain metastases is comparable to that in patients without distant organ metastases. There were two cases with specific fusion types that also responded to alectinib; namely, double ALK-rearrangements: EML4-ALK (E13:A20) and MSH2-ALK (M7:A20), and with a rare fusion partner, SPECC1L-ALK (S8:A20). Their PFS were 8.7 and 38.0 months, respectively.

Conclusions: In this study, the efficacy of alectinib in different types of ALK-rearrangements varied slightly. TP53 and TSC1 co-mutations were identified as detrimental factors affecting efficacy. This study provides references for the response to alectinib in patients with different types of ALK rearrangements and co-mutation.

Keywords: Non-small cell lung cancer (NSCLC); alectinib; anaplastic lymphoma kinase (ALK); chromosomal rearrangements; co-mutated genes.

Figure 1

The OncoPrint of the somatic SNVs in 66 patients in our study. The genes are ranked by the frequency of the mutations across all samples. PD-L1, programmed cell death ligand 1; NA, not applicable; SNV, single nucleotide variant.

Figure 2

Analysis of ALK-rearrangement types. (A) Different ALK-rearrangement types in LADC patients. (B) BOR analysis on EML4-ALK (E6:A20), EML4-ALK (E13:A20), and EML4-ALK (E20:A20). EML4, echinoderm microtubule-associated protein-like 4; ALK, anaplastic lymphoma kinase; PR, partial response; SD, stable disease; PD, progressive disease; LADC, lung adenocarcinoma; BOR, best overall response.

Figure 3

PFS analysis. (A) PFS for the whole cohort. (B) Three-year PFS rates for the entire cohort. (C) PFS of patients with different ALK-rearrangement types in LADC. (D) Three-year PFS rates for different fusion types. (E) PFS data for each patient. PFS, progression-free survival; m, months; EML4, echinoderm microtubule-associated protein-like 4; ALK, anaplastic lymphoma kinase; LADC, lung adenocarcinoma.

Figure 4

Co-mutation analysis. (A) Analysis of PFS carrying different types of co-mutations. (B) Analysis of PFS in patients with and without TP53 co-mutations. (C) Analysis of PFS in patients with and without TSC1 co-mutations. (D) Therapeutic effect (PD, PR, and SD) analysis on patients with different types of co-mutations. PFS, progression-free survival; m, months; NA, not applicable; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 5

Efficacy of alectinib in patients with or without Specific metastasis site. (A) PFS of alectinib treatment in patients with different metastatic sites. (B) BOR of patients with different metastatic sites. PFS, progression-free survival; m, months; PD, progressive disease; PR, partial response; SD, stable disease; BOR, best overall response.

Figure 6

The therapeutic schedule of patient 1. (A) The details of therapeutic schedule. (B,C) CT images of patient 1. LADC, lung adenocarcinoma; ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; D2, twice a day; PR, partial response; CT, computed tomography.

Figure 7

The therapeutic schedule of patient 2. (A) The details of therapeutic schedule. (B-E) CT images of patient 2. LADC, lung adenocarcinoma; ALK, anaplastic lymphoma kinase; CT, computed tomography; PR, partial response; PD, progressive disease; SD, stable disease; D2, twice a day; AC, pemetrexed/carboplatin.